Field of the Invention
The present invention relates generally to the fields of obesity and metabolic disorders. More specifically, the present invention discloses the use of interleukin-25 to treat obesity and metabolic disorders including diabetes and hepatic steatosis.
Description of the Related Art
The incidence of obesity has increased dramatically worldwide and has risen to endemic level in U.S., with over one-third of the adult American population being obese. Multiple factors contribute to obesity including genetic predisposition, environmental, socioeconomic, and behavioral factors. In addition, obesity is one of the key etiological factors for many metabolic diseases such as diabetes, hypertension, heart disease. Obesity is accompanied with chronic low grade inflammation in adipose tissues, mainly due to the accumulated inflammatory cells (Th1/Th17 cells, macrophages, etc), which, together with adipocytes, release variety of proinflammatory cytokines/chemokines that contribute to the development of the metabolic syndrome and exacerbation of obesity.
Among the infiltrated inflammatory cells in adipose tissue, macrophages are involved in the development of obesity-associated tissue inflammation and metabolic dysfunction. Depending on the cytokine microenvironment, macrophages undergo distinct pathways of activation and display different phenotypes: the classically-activated macrophages (M1) that are induced by the Th1 cytokine and characterized by the production of nitric oxide (NO) through inducible nitric oxide synthase (NOS-2), and the alternatively-activated macrophages (M2) induced by Th2 cytokines, IL-4 and IL-13, and characterized by highly up regulated arginase I, mannose receptor (CD206), as well as the secretion of chitinase and “found in inflammatory zone” (FIZZ) family members as YM1, FIZZ1, and FIZZ23. Obese adipose tissue usually contains more macrophages or adipose tissue macrophages (ATMs) than lean adipose tissue. In addition, more of those adipose tissue macrophages in obese tissue exhibit M1, a pro-inflammatory phenotype, rather than M2, an anti-inflammatory phenotype, resulting in an increased production of pro-inflammatory cytokines such as IL-6 and TNFα, and less production of the anti-inflammatory cytokines such as IL-10 and TGF-β2.
Besides macrophages, various subsets of lymphocytes are also found in the stromal vascular fraction of adipose tissue. A recent study showed that there is a CD8+ T cell infiltration preceding the accumulation of macrophages in obese adipose tissue and these CD8+ T cells participate in macrophage differentiation, activation, and migration. CD4+ Th1 cells may also help recruit macrophages into adipose tissue and stimulate the M1 macrophage inflammatory activation. In addition, these CD4+ cells can respond to specific antigen generated in obese adipose tissue to produce inflammatory Th1 cytokines. Meanwhile, the number of T regulatory cells, which have inhibitory effects on inflammation, is usually decreased in obese adipose tissue. As a result of all these combined factors, large amount of pro-inflammatory cytokines are produced in adipose tissue and released to circulation, which in turn cause insulin resistance as well as other metabolic syndromes. IL-25, also called IL-17E, is a cytokine member of IL-17 family. While other members of the IL-17 family, especially IL-17A and IL-17F, have biological activities similar to Th1 inflammatory cytokines, IL-25 is involved primarily in the promotion of Th2 immunity, including allergy, asthma, and enteric nematode infection. Of equal importance is that IL-25 also inhibits pro-inflammatory Th1 and Th17 cytokine responses. Therefore, IL-25 is emerging as a key regulator of inflammation in the gut mucosa. It has been shown that IL-25 expression is up-regulated in the gut following nematode infection and the up-regulation depends upon IL-13 activation of STAT67. In addition, epithelial cells, but not immune cells, constitute the major source of IL-25 in the gut, implicating the important role of epithelium-derived factors in the induction of Th2 immunity.
Therefore, the prior art is deficient in methods of treating obesity, obesity related disorders and metabolic disorders. The present invention fulfills this long-standing need and desire in the art.